How successful are AI-discovered drugs in clinical trials? A first analysis and emerging lessons.

AI techniques are making inroads into the field of drug discovery. As a result, a growing number of drugs and vaccines have been discovered using AI. However, questions remain about the success of these molecules in clinical trials. To address these questions, we conducted a first analysis of the clinical pipelines of AI-native Biotech companies. In Phase I we find AI-discovered molecules have an 80-90% success rate, substantially higher than historic industry averages. This suggests, we argue, that AI is highly capable of designing or identifying molecules with drug-like properties. In Phase II the success rate is ∼40%, albeit on a limited sample size, comparable to historic industry averages. Our findings highlight early signs of the clinical potential of AI-discovered molecules.

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

The Swiss Atlas of Health Care: monitoring variations in care to improve health care delivery in Switzerland.

No abstract available.

Utilisation patterns and costs of lipid-lowering drugs in Switzerland 2013-2019.

OBJECTIVE: To analyse utilisation patterns of lipid-lowering drugs and the related costs in Switzerland between the years 2013 and 2019. METHODS: We conducted a retrospective descriptive study using administrative claims data of persons aged ≥18 years enrolled with the health insurance company Helsana. To enable statements at the Swiss population level, results were extrapolated according to age, sex and canton of residence. RESULTS: The overall prevalence of patients taking lipid-lowering drugs rose from 8.9% (n = 736,174) in 2013 to 11.6% (n = 841,682) in 2019, but varied markedly across regions, with highest values in Ticino and lowest values in Zurich. More than every third individual aged ≥65 years was treated with a lipid-lowering drug in 2019. Statins were by far the most commonly used drugs (>90% of prescriptions), followed by ezetimibe, fibrates and PCSK9 inhibitors. We observed a trend towards the prescription of more potent statins (atorvastatin, rosuvastatin) in recent years. Total costs of lipid-lowering drugs increased from CHF 222 million in 2013 to CHF 230 million in 2019 (+3.5%), whereas annual per capita costs decreased from CHF 302 in 2013 to CHF 273 in 2019 (-9.4%). CONCLUSION: The increasing use of lipid-lowering drugs reflects current therapeutic guidelines, but results in high costs for the healthcare system.

Systematic screening on admission for SARS-CoV-2 to detect asymptomatic infections.

The proportion of asymptomatic carriers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains elusive and the potential benefit of systematic screening during the SARS-CoV-2-pandemic is controversial. We investigated the proportion of asymptomatic inpatients who were identified by systematic screening for SARS-CoV-2 upon hospital admission. Our analysis revealed that systematic screening of asymptomatic inpatients detects a low total number of SARS-CoV-2 infections (0.1%), questioning the cost-benefit ratio of this intervention. Even when the population-wide prevalence was low, the proportion of asymptomatic carriers remained stable, supporting the need for universal infection prevention and control strategies to avoid onward transmission by undetected SARS-CoV-2-carriers during the pandemic.

Drug prescription patterns, polypharmacy and potentially inappropriate medication in Swiss nursing homes: a descriptive analysis based on claims data.

BACKGROUND: To date, comprehensive data on drug utilisation in Swiss nursing homes are lacking. OBJECTIVE: To describe drug prescription patterns, polypharmacy and potentially inappropriate medication (PIM) in Swiss nursing home residents (NHR). METHODS: Using administrative claims data provided by the Swiss health insurance company Helsana, we assessed drug claims and drug costs in 2016 in individuals aged ≥65 years and insured with Helsana, who were either NHR or living in the community (reference group, RG). In particular, we analysed the prevalence of polypharmacy (≥5 claims for different drugs during a 3-month period) and PIM use according to the 2015 Beers criteria and the PRISCUS list. We standardised the results to the Swiss population. RESULTS: In 2016, NHR had on average nearly twice as many drug claims per capita as individuals in the RG (NHR 58.8; RG 30.8). The average per capita drug costs per day for NHR were low, but higher than in the RG (NHR CHF 8.55; RG CHF 5.45). The same pattern applied to the prevalence of polypharmacy (NHR 85.5%; RG 50.4%). Standardisation by age and sex did not materially alter these observations. Overall, 79.1% of NHR received ≥1 PIM, and 56.2% were long-term users (≥3 claims) of at least one PIM (based on the combined PRISCUS list and Beers criteria). Among all PIMs in nursing homes, quetiapine (antipsychotic agent), lorazepam (anxiolytic agent) and zolpidem (hypnotic agent) were the most prevalent (22.4, 20.2 and 13.0%, respectively). CONCLUSIONS: The high prevalence of polypharmacy and PIM in Swiss nursing homes may indicate a need for interventions aiming at de-prescribing drugs with an unfavourable benefit-risk profile.

Medication-related problems during transfer from hospital to home care: baseline data from Switzerland.

Background The shift from inpatient to ambulatory care has resulted in an increase in home care patients. Little is known regarding medication safety associated with patient transfer from hospital to home care. Objective To evaluate medication-related problems in patients transferring from hospital to home care in Switzerland. Setting A non-for-profit home care organization in the city of Lucerne/Switzerland. Methods We conducted a prospective observational study, including patients aged ≥ 64 years and receiving ≥ 4 medications at hospital discharge. Two structured questionnaires assessing the transfer process were completed by home care nurses. Prescription quality was assessed using a PCNE Type 2b Medication Review. Main outcome measures The quality of the transfer process was measured comparing agreed-upon with reported parameters. Prescription quality was analyzed assessing the unambiguity of the prescription. Potentially inappropriate medications (Priscus® list), contraindications, duplications and interactions, and clinical pharmacist-identified potential medication-related problems were collected. Results Study patients (n = 100) received 8.6 ± 3.5 regularly administered medications. Only 5/100 patients had a complete set of written discharge information. At the time of the first visit, 13/100 patients had no written medication information available. Discharge medication prescriptions were clear to nurses in 62% of patients. In 20 patients, the required medications were unavailable, resulting in 19 medication errors. Assessment by a clinical pharmacist revealed only 33/100 patients had a clear discharge prescription. Of a total of 984 prescribed drugs, 16% were considered to be ambiguous, 22 (2.2%) were potentially inappropriate. 7/984 drugs were contraindicated, 8 were duplicates. Conclusion In addition to the known risk factors in patients transferring from hospital to home care (age, polymedication, multiple providers), 3 major problems impacted upon medication safety: fragmented communication, unreliable medication availability and a poor prescription quality. Clinical pharmacists are an important option to improve medication safety ass.

Glucocorticoids and the Risk of Peptic Ulcer Bleeding: Case-Control Analysis Based on Swiss Claims Data.

INTRODUCTION: Controversy exists as to whether glucocorticoids (GC) are ulcerogenic per se and may thus cause peptic ulcer bleeding (PUB) independent of concomitantly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: To investigate the association between GC use and PUB with or without co-medication with NSAIDs. METHODS: We conducted a case-control study using administrative claims data from the Swiss health insurance company Helsana. We identified 1191 cases with incident PUB between 2012 and 2016 and matched up to 10 PUB-free controls to each case on age, sex, region and number of years insured with Helsana. We compared prior GC exposure between cases and controls using multivariate conditional logistic regression analyses controlling for several potential confounders. Patients with or without concomitant NSAID exposure were analysed separately. RESULTS: Patients with prior exposure to both GC and NSAIDs were five times more likely to experience PUB than patients who neither used GC nor NSAIDs (adjusted odds ratio [adj. OR] 4.80, 95% CI 3.55-6.71). Although the risk of PUB among patients who used NSAIDs without GC was increased threefold (adj. OR 3.20, 95% CI 2.59-3.95), we observed only a moderately increased risk among patients who used GC alone without NSAIDs (adj. OR 1.63, 95% CI 1.20-2.42). CONCLUSIONS: The use of NSAIDs with or without GC was associated with a markedly higher risk of PUB compared with GC monotherapy. Use of GC alone was associated with a moderately increased risk of PUB, which might be causal or attributed to confounding by indication.

Preliminary Results of a Novel Algorithmic Method Aiming to Support Initial Causality Assessment of Routine Pharmacovigilance Case Reports for Medication-Induced Liver Injury: The PV-RUCAM.

INTRODUCTION: Data incompleteness in pharmacovigilance (PV) health records limits the use of current causality assessment methods for drug-induced liver injury (DILI). In addition to the inherent complexity of this adverse event, identifying cases of high causal probability is difficult. OBJECTIVE: The aim was to evaluate the performance of an improved, algorithmic and standardised method called the Pharmacovigilance-Roussel Uclaf Causality Assessment Method (PV-RUCAM), to support assessment of suspected DILI. Performance was compared in different settings with regard to applicability and differentiation capacity. METHODS: A PV-RUCAM score was developed based on the seven sections contained in the original RUCAM. The score provides cut-off values for or against DILI causality, and was applied on two datasets of bona fide individual case safety reports (ICSRs) extracted randomly from clinical trial reports and a third dataset of electronic health records from a global PV database. The performance of PV-RUCAM adjudication was compared against two standards: a validated causality assessment method (original RUCAM) and global introspection. RESULTS: The findings showed moderate agreement against standards. The overall error margin of no false negatives was satisfactory, with 100% sensitivity, 91% specificity, a 25% positive predictive value and a 100% negative predictive value. The Spearman's rank correlation coefficient illustrated a statistically significant monotonic association between expert adjudication and PV-RUCAM outputs (R = 0.93). Finally, there was high inter-rater agreement (K w = 0.79) between two PV-RUCAM assessors. CONCLUSION: Within the PV setting of a pharmaceutical company, the PV-RUCAM has the potential to facilitate and improve the assessment done by non-expert PV professionals compared with other methods when incomplete reports must be evaluated for suspected DILI. Prospective validation of the algorithmic tool is necessary prior to implementation for routine use.

Benzodiazepine Use and Risk of Developing Alzheimer's Disease: A Case-Control Study Based on Swiss Claims Data.

BACKGROUND: A possible association between benzodiazepine use and Alzheimer's disease (AD) has been hypothesized in previous studies. OBJECTIVES: Using claims data from the Helsana Group, a large Swiss health insurance provider, we examined the association between previous benzodiazepine use and the risk of AD. METHODS: We conducted a matched case-control study and identified 1438 incident AD cases between 2013 and 2014 based on recorded first-time use of drugs used to treat AD [i.e., acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate receptor antagonist memantine] and matched one control to each case on age, sex, index date, and residence (canton). Because the initiation of benzodiazepine use shortly before the AD diagnosis date may occur as a result of symptomatic treatment of prodromal symptoms of early major neurocognitive disorder, we introduced an induction period of 2 years before the AD diagnosis date. Additionally, we categorized medication use by duration of use prior to the index date using prescriptions. We applied conditional logistic regression analyses to calculate odds ratios with 95% confidence intervals and adjusted for use of antidepressants. RESULTS: The crude odds ratio (95% confidence interval) of developing AD for patients starting benzodiazepine treatment was 1.71 (1.17-2.99) in the year before diagnosis and 1.19 (0.82-1.72) in the third year before diagnosis. After accounting for benzodiazepine use initiated during the prodromal phase, benzodiazepine use was not associated with an increased risk of developing AD; long-term benzodiazepine use (≥30 prescriptions) yielded an adjusted odds ratio of 0.78 (0.53-1.14). CONCLUSIONS: After taking into consideration a possible protopathic bias in the 2 years preceding the AD diagnosis date, benzodiazepine use was not associated with an increased risk of developing AD.

Effects of enamel abrasion, salivary pellicle, and measurement angle on the optical assessment of dental erosion.

The present study assessed the effects of abrasion, salivary proteins, and measurement angle on the quantification of early dental erosion by the analysis of reflection intensities from enamel. Enamel from 184 caries-free human molars was used for in vitro erosion in citric acid (pH 3.6). Abrasion of the eroded enamel resulted in a 6% to 14% increase in the specular reflection intensity compared to only eroded enamel, and the reflection increase depended on the erosion degree. Nevertheless, monitoring of early erosion by reflection analysis was possible even in the abraded eroded teeth. The presence of the salivary pellicle induced up to 22% higher reflection intensities due to the smoothing of the eroded enamel by the adhered proteins. However, this measurement artifact could be significantly minimized (p<0.05) by removing the pellicle layer with 3% NaOCl solution. Change of the measurement angles from 45 to 60 deg did not improve the sensitivity of the analysis at late erosion stages. The applicability of the method for monitoring the remineralization of eroded enamel remained unclear in a demineralization/remineralization cycling model of early dental erosion in vitro.

Costs of dispersal.

Dispersal costs can be classified into energetic, time, risk and opportunity costs and may be levied directly or deferred during departure, transfer and settlement. They may equally be incurred during life stages before the actual dispersal event through investments in special morphologies. Because costs will eventually determine the performance of dispersing individuals and the evolution of dispersal, we here provide an extensive review on the different cost types that occur during dispersal in a wide array of organisms, ranging from micro-organisms to plants, invertebrates and vertebrates. In general, costs of transfer have been more widely documented in actively dispersing organisms, in contrast to a greater focus on costs during departure and settlement in plants and animals with a passive transfer phase. Costs related to the development of specific dispersal attributes appear to be much more prominent than previously accepted. Because costs induce trade-offs, they give rise to covariation between dispersal and other life-history traits at different scales of organismal organisation. The consequences of (i) the presence and magnitude of different costs during different phases of the dispersal process, and (ii) their internal organisation through covariation with other life-history traits, are synthesised with respect to potential consequences for species conservation and the need for development of a new generation of spatial simulation models.

Systematic review of medication safety assessment methods.

PURPOSE: The accuracy, efficiency, and efficacy of four commonly recommended medication safety assessment methodologies were systematically reviewed. METHODS: Medical literature databases were systematically searched for any comparative study conducted between January 2000 and October 2009 in which at least two of the four methodologies-incident report review, direct observation, chart review, and trigger tool-were compared with one another. Any study that compared two or more methodologies for quantitative accuracy (adequacy of the assessment of medication errors and adverse drug events) efficiency (effort and cost), and efficacy and that provided numerical data was included in the analysis. RESULTS: Twenty-eight studies were included in this review. Of these, 22 compared two of the methodologies, and 6 compared three methods. Direct observation identified the greatest number of reports of drug-related problems (DRPs), while incident report review identified the fewest. However, incident report review generally showed a higher specificity compared to the other methods and most effectively captured severe DRPs. In contrast, the sensitivity of incident report review was lower when compared with trigger tool. While trigger tool was the least labor-intensive of the four methodologies, incident report review appeared to be the least expensive, but only when linked with concomitant automated reporting systems and targeted follow-up. CONCLUSION: All four medication safety assessment techniques-incident report review, chart review, direct observation, and trigger tool-have different strengths and weaknesses. Overlap between different methods in identifying DRPs is minimal. While trigger tool appeared to be the most effective and labor-efficient method, incident report review best identified high-severity DRPs.

Bacterial community structure of a pesticide-contaminated site and assessment of changes induced in community structure during bioremediation.

The introduction of culture-independent molecular screening techniques, especially based on 16S rRNA gene sequences, has allowed microbiologists to examine a facet of microbial diversity not necessarily reflected by the results of culturing studies. The bacterial community structure was studied for a pesticide-contaminated site that was subsequently remediated using an efficient degradative strain Arthrobacter protophormiae RKJ100. The efficiency of the bioremediation process was assessed by monitoring the depletion of the pollutant, and the effect of addition of an exogenous strain on the existing soil community structure was determined using molecular techniques. The 16S rRNA gene pool amplified from the soil metagenome was cloned and restriction fragment length polymorphism studies revealed 46 different phylotypes on the basis of similar banding patterns. Sequencing of representative clones of each phylotype showed that the community structure of the pesticide-contaminated soil was mainly constituted by Proteobacteria and Actinomycetes. Terminal restriction fragment length polymorphism analysis showed only nonsignificant changes in community structure during the process of bioremediation. Immobilized cells of strain RKJ100 enhanced pollutant degradation but seemed to have no detectable effects on the existing bacterial community structure.

Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure.

Interleukin (IL)-1 is a regulator of inflammation but is also implicated in the control of energy homeostasis. Because the soluble IL-1 receptor antagonist (IL-1Ra) is markedly increased in the serum of obese patients and is overexpressed in white adipose tissue in obesity, we studied the metabolic consequences of genetic IL-1Ra ablation in mice. We have shown that IL-1Ra-/- mice have a lean phenotype due to decreased fat mass, related to a defect in adipogenesis and increased energy expenditure. The adipocytes were smaller in these animals, and the expression of genes involved in adipogenesis was reduced. Energy expenditure as measured by indirect calorimetry was elevated, and weight loss in response to a 24-h fast was increased in IL-1Ra-/- animals compared with wild-type mice. Lipid oxidation of IL-1Ra-/- mice was higher during the light period, reflecting their reduction in diurnal food intake. Interestingly, IL-1Ra-/- and IL-1Ra+/- mice presented an attenuation in high-fat diet-induced caloric hyperphagia, indicating a better adaptation to hypercaloric alimentation, which is in line with the role of IL-1Ra as a mediator of leptin resistance. Taken together, we show that IL-1Ra is an important regulator of adipogenesis, food intake, and energy expenditure.